Gary J. Schiller, MD

Director, Bone Marrow/Stem Cell Transplantation

Professor, Hematology-Oncology

David Geffen School of Medicine at UCLA

Los Angeles, CA

I have a lot of patients in my clinic with [BPDCN], but in general, it is a rare disease [that clinicians] may not see for many years in their practice. Its true epidemiology is not known because [clinicians] didnt know how to identify it, so it is historically rare. To make it even more difficult, there was a change in nomenclature by the [World Health Organization] back in 2016.1 A lot of older practitionersand Im one of those older practitionerswould call this [disease] some sort of lymphoid leukemia with cutaneous manifestations.

There is a lot of difficulty in recognizing this disease clinically and pathologically, and its more recent that [the targets of] CD4, CD56, and CD123 expression [were] all identified as pathognomonic.2 Right now, we think this constitutes less than half a percent of all hematologic malignancies and less than a percent of [patients with] cutaneous lymphoma.

We believe there are [approximately] 4 cases per 10 million population, so that gives you an idea of rarity, but I think that we dont know because we havent had a strong diagnostic bed of criteria until [approximately] 2016. Weve been doing this for [approximately] 5 or 6 years, and knowledge will increase when weve gone past a decade with homogeneous diagnostic criteria.

How BPDCN Presents

[This disease] is characterized by production of clonal plasmacytoid dendritic cells. These cells are characteristic with their expression pattern and are a little more common in the older population, even [for patients older than] 70 years.3

Many of the patients are older men, but not exclusively, as Im taking care of a young [woman] right now [who is] in her 30s, so this epidemiology is also bound to change if they have an antecedent hematologic disorder that is rare.

The primary sits of involvement are skin, bone marrow, peripheral blood, lymph nodes, leptomeninges, and extramedullary sites such as in the muscle behind the retroperitoneum also occur. Early recognition is challenging, as the clinical features are also challenging and can overlap with other diseases, and there are delays between the onset of the skin rash and the diagnosis.

[Those] who see this in the field are internists, dermatologists, and hematologists and oncologists after a while, [and they can miss] this diagnosis unfortunately. The typical journey for a patient with this condition is that they start having continuous lesions and are then examined by a primary care physician for a while, and they may or may not be identified as having something that requires immediate biopsy evaluation. When the patient develops pancytopenia, thats when the referral occurs, and the median time to final diagnosis is often 6 months.

However, this disease is highly aggressive when its not treated with specific agents, and the survival is 6 to 18 months.4 [Clinicians] have tried all kinds of treatments, such as vincristine, steroids, treating it like its acute lymphocytic leukemia, or treating it now like one would acute myeloid leukemiawith venetoclax [Venclexta] and azacitidine [Onureg]. But without specific therapy, the survival is short.

Cutaneous Features of BPDCN

The cutaneous features vary a little, but most patients present with some nodule that is described as dark purple, brown, or [bruised]. Sometimes they can have plaques, but I view them as basically little hemorrhages that are in the form of nodules or plaques that are often disseminated, typically sparing the dermis.

Skin biopsies that include the deep dermis and subcutaneous fat are very important to making a diagnosis, but as I say, usually the disease involves the peripheral blood and bone marrow, so there are easier ways to make a diagnosis than taking a deep tissue biopsy.4

Some of our patients do have localized manifestations and a localized geography. The other differential diagnoses include extramedullary hematopoiesis and some malignant neoplasms. This disease can spread broadly like a leukemia, and its not unusual for patients to have splenomegaly. What Im dealing with right now with a patient of mine is leptomeningeal involvement with cranial neuropathy. That is not a rare thing, [its a] typical kind of leptomeningeal leukemia in that patients have cranial nerve findings at the base of the brain.5

Other sites of the disease include sinus, tongue, breast tissue, gallbladder, [and] muscle, so this disease can spread broadly. Initial evaluationof course, besides the usual history, physical, and blood countwould be an assessment of the skin lesions in terms of how disparate they are and [whether] there are any hints of blood involvement, cytopenias, leukocytosis with blasts, or bone marrow aspirate biopsy, because it would be the easiest way to make a diagnosis.

Evaluations of BPDCN

The molecular analysis by sequencing frequently identifies mutations in the typical older personkind of clonal hematopoiesis ASXL1 but also U2AF1 [and] things like TP53 [are] quite adverse, as well as occasionally IDH or IKZF1.

A PET CT is a good idea if [the clinician] suspects there is extensive extramedullary disease or adenopathy [theyd] like to follow. [There is also a recommendation for] diagnostic lumbar puncture at the time of diagnosis, but we typically do it at the time of relapse.

The [National Comprehensive Cancer Networks] set of guidelines for the evaluation and workup drives home the characteristic findings on histopathology, immunohistochemistry, and flow cytometry.6 Of course, if [someone is] in a center where this disease is uncommon, its certainly worthwhile to speak to [clinicians] who have experience with it and have participated in some of the trials or used the licensed medication.

In the peripheral blood, these cells look a little [like] lymphoid. Its common to find peripheral blood involvement in this disease, although maybe not quite in the leukemic phase. As Ive described before, these blasts are large, nuclear chromatin is open, nuclei are typically present, and the cytoplasm is not granular, so it doesnt look like myeloid leukemia. [However], monocytic leukemia can look similar and typically doesnt have much in the way of granulesand there are no vacuoles, so its not like Burkitt lymphoma.

There is no particular characteristic of a cytogenetic abnormality in BPDCN, but there are abnormalities [such as] deletions of the monosomy 5 and 6 or 13 and 15. The molecular abnormalities are also varied, and findings in a common older patient [can include] TET2 and ASXL1. But TP53, the adverse finding, is also common, as well as occasionally NPM1.

CD123 is a perfect marker because its present in over 95% of patients cells in the malignant neoplasm, and it is not so heavily expressed on healthy cells.7 This also has constituted a target for therapy because of the relative distribution of that marker on neoplastic cells, but there arent typical T-cell or B-cell markers.8

Treatment Paradigm in BPDCN

Tagraxofusp [Elzonris] is a typical immunotoxin and a CD123-directed antibody. That CD123 is the IL-3 alpha receptor, and attached to it is a payload of truncated diphtheria toxin, which is delivered into the cell that has this receptor. Its a first-in-class CD123-targeted immunotherapeutic and is FDA approved for [the] treatment of [patients with] BPDCN.9

Patients who have impaired performance status can get other treatments like localized treatment [such as] radiation or venetoclax-based therapy. Somebody who is protein malnourished would not be a candidate for tagraxofusp because this drug causes capillary leak, so there is a warning in the label, and patients with serum albumin less than 3.2 g/dL are not eligible for treatment. [However], on that treatment with steroids, they can get their albumin to improve by improving their performance status [and] increasing their appetite and food intake.

[The approval for the therapy came from the] multicenter, 4-stage, single arm, phase 1/2 trial [NCT02113982] evaluating this drug as monotherapy in patients with first-line or relapsed/refractory BPDCN, administered via intravenous infusion daily from day 1 through 5 for a 21-day cycle.10

The key eligibility criteria for the trial included albumin greater than or equal to 3.2 g/dL, age greater than or equal to 18 [years], a reasonably good performance status of less than or equal to 2, and adequate organ function. The primary end point was a combined rate of complete remission [CR] and CR with residual skin abnormality [CRc] in first-line patients.

The secondary end point was the duration or response [of treatment] and CR with residual skin abnormality not indicative of active disease. Some of these patients will have resolution of the nodule, but pigmentation that might remain, which didnt exclude them from being complete remitters.

Twenty-nine patients were previously untreated in the first line, the overall response rate [ORR] was 90% in stages 1 to 3, and the CR and CRc rate was 72%. Of those previously treated, many had more than 1 line of therapy, [with] some even having more than 4 lines of therapy.

Overall, the ORR was 75%, and many of these patients went on to stem cell transplant, but the impact of the drug on survival is harder to assess when you use allogeneic stem cell transplant as a consolidated maneuver.

[However], the overall likelihood of remaining in remission at 2 years was [approximately] 50% of those who went into remission. The median duration of CR and CRc was less than 3 years, and the median overall survival for all patients [was 8.2 months (95% CI, 4.1-11.9)].

Adverse Events With Tagraxofusp

The adverse event [AE] profile is important [with this therapy], and AEs occurring in at least 20% of patients included transaminase elevations [64%], peripheral edema [42%], weight increase [35%], hypokalemia [20%], and hypocalcemia [20%].

AEs that led to discontinuation were predominantly the capillary leak syndrome type, an increase in weight, and a decrease in albumin. [However], AST [aspartate aminotransferase] and ALT [alanine aminotransferase] increase also led to discontinuations.

Fortunately, discontinuations were not common on the trial, with only 6 of 89 [patients]. Again, however, to point out for those who had at least 1 grade greater than or equal to grade 3, treatment-emergent AEs were identified in 75 of 89 patients, with the most common grade 3 or great AEs [being] thrombocytopenia and [fewer] AST and ALT increases.

The overall incidence of capillary leak syndrome was high, over 50%. Most were grade 1 to 2 and resolved but some were not, including 2 fatal events, so you need to watch this. The first cycle must be given in the hospital. Common signs and symptoms include hypoalbuminemia, edema, weight gain, and hypotension.

Before initiating therapy, make sure the patient has adequate cardiac function and that the serum albumin is over 3.2 g/dL. During treatment, ensure that serum albumin levels stay above 3.5 g/dL and have not dropped by more than half an albumin level prior to initiation of each dose. Assess for signs and symptoms of capillary leaks, such as weight gain, new onset or worsening edema, pulmonary edema, hypotension, [and] hemodynamic instability. Seek medical advice if you see any of these things.

REFERENCES

Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544

Deconinck E, Petrella T, Garnache Ottou F. Blastic plasmacytoid dendritic cell neoplasm: clinical presentation and diagnosis. Hematol Oncol Clin North Am. 2020;34(3):491-500. doi:10.1016/j.hoc.2020.01.010

Pemmaraju N. Blastic plasmacytoid dendritic cell neoplasm. Clin Adv Hematol Oncol. 2016;14(4):220-222.

Julia F, Petrella T, Beylot-Barry M, et al. Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients. Br J Dermatol. 2013;169(3):579-586. doi:10.1111/bjd.12412

Pemmaraju N, Wilson NR, Khoury JD, et al. Central nervous system involvement in blastic plasmacytoid dendritic cell neoplasm. Blood. 2021;138(15):1373-1377. doi:10.1182/blood.2021011817

NCCN. Clinical Practice Guidelines in Oncology. Blastic plasmacytoid dendritic cell neoplasm, version 2.2022. Accessed February 22, 2023. https:// bit.ly/3ZgDzbM

Molina Castro D, Perilla Surez O, Cuervo-Sierra J, Moreno A. Blastic plasmacytoid dendritic cell neoplasm with central nervous system involvement: a case report. Cureus. 2022;14(4):e23888. doi:10.7759/cureus.23888

Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628-1637. doi:10.1056/ NEJMoa1815105

FDA approves tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. FDA. December 26, 2018. Accessed February 22, 2023. https:// bit.ly/3YWJ5Rb

Pemmaraju N, Sweet KL, Stein AS, et al. Long-term benefits of tagraxofusp for patients with blastic plasmacytoid dendritic cell neoplasm. J Clin Oncol. 2022;40(26):3032-3036. doi:10.1200/JCO.22.00034

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